Antigen receptor–mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth

Abstract

The bioenergetic response of B lymphocytes is subject to rapid changes following antigen encounter in order to provide ATP and anabolic precursors necessary to support growth. However, the pathways involved in glucose acquisition and metabolism are unknown. We find that B lymphocytes rapidly increase glucose uptake and glycolysis following B-cell antigen receptor (BCR) crosslinking. Inhibition of glycolysis blocks BCR-mediated growth. Prior to S-phase entry, glucose metabolism shifts from primarily glycolytic to include the pentose phosphate pathway. BCR-induced glucose utilization is dependent upon phosphatidylinositol 3-kinase (PI-3K) activity as evidenced by inhibition of glucose uptake and glycolysis with LY294002 treatment of normal B cells and impaired glucose utilization in B cells deficient in the PI-3K regulatory subunit p85␣. Activation of Akt is sufficient to increase glucose utilization in B cells. We find that glucose utilization is inhibited by coengagement of the BCR and Fc␥RIIB, suggesting that limiting glucose metabolism may represent an important mechanism underlying Fc␥RIIB-mediated growth arrest. Taken together, these findings demonstrate that both growth-promoting BCR signaling and growth-inhibitory Fc␥RIIB signaling modulate glucose energy metabolism. Manipulation of these pathways may prove to be useful in the treatment of lymphoproliferative disorders, wherein clonal expansion of B lymphocytes plays a role. IntroductionIn response to antigen challenge, resting B lymphocytes exit the G 0 phase of the cell cycle and undergo a period of growth before committing to genome replication. 1,2 Growth corresponds to an accumulation of cell mass that is accompanied by increased size and is linked to increased de novo macromolecular synthesis. [3][4][5] That mammalian cell growth may be necessary for genome replication underscores its importance in adaptive immunity in that the clonal expansion of antigen-specific B lymphocytes is a prerequisite for humoral immune responses. Most investigations in B cells have focused on the role of genes whose function are important for B-cell antigen receptor (BCR)-induced protein synthesis and increased cell size. 4,5 It is recognized, however, that antigen receptor-triggered macromolecular synthesis and gene expression places enormous bioenergetic demands on lymphocytes. 5,6 Therefore, one of the fundamental aspects of B-cell responses to antigen challenge that may be critical in vivo is the provision of metabolic substrates to provide ATP and anabolic precursors for cellular growth.Early studies in lectin-stimulated thymocytes highlighted the importance of glucose uptake and catabolism in providing energy and carbon for macromolecular synthesis. 7,8 Further, proliferating thymocytes meet their ATP demand mainly by glycolytic catabolism when sufficient glucose is available. 9 It is widely viewed that glucose metabolism is regulated by homeostatic mechanisms wherein mammalian cells respond to a decreased ATP/ADP ratio by adjusting nutrient uptake and catabolism t...

The effect of Monocarboxylate Transporter (MCT1) inhibitor, AR-C117977 on accelerated rejection of cardiac grafts in pre-sensitised rats and concordant xenotransplantation

“…These data suggest that activated B-lymphocytes have a high rate of aerobic glycolysis leading to lactate production such that inhibition of lactate efflux by MCT1 blockade reduces the ability of the cells to proliferate and produce antibodies. The dependence of activated T-lymphocytes on aerobic glycolysis (the Warburg effect) has now been established [12] but the metabolic processes required for B-lymphocyte activation and function have not been widely investigated although increased glucose metabolism after activation has been shown [13]. Our study provides evidence that MCT blockade can affect the function of B-lymphocytes in vitro and in vivo in addition to causing immunosuppression via inhibition of T-lymphocyte proliferation as we have previously described [4].…”

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

“…Emerging evidence indicates that upon antigen encounter, B cells reprogram metabolism to meet the biosynthetic demands for antibody production (Capasso et al, 2015;Caro-Maldonado et al, 2014;Doughty et al, 2006;Le et al, 2012). Activation of B cells is accompanied by increased glycolysis and glutaminolysis (Buck et al, 2015;Caro-Maldonado et al, 2014;Dufort et al, 2007;Woodland et al, 2008).…”

“…Activation of B cells is accompanied by increased glycolysis and glutaminolysis (Buck et al, 2015;Caro-Maldonado et al, 2014;Dufort et al, 2007;Woodland et al, 2008). In order to build new biomass, activated B cells increase the import of necessary nutrients, such as glucose, and promote their utilization (Caro-Maldonado et al, 2014;Doughty et al, 2006). In addition to glucose, activated B cells need amino acids for synthesis of antibodies and other proteins, as well as nitrogen, for nucleotide synthesis and other processes (Calder, 2006;Grohmann and Bronte, 2010).…”

Glucose-dependent de Novo Lipogenesis in B Lymphocytes

“…Small dense B cells were isolated following centrifugation through a discontinuous 72:65:50% Percoll gradient. B cells were cultured in RPMI 1640 medium (Mediatech, Inc., Manassas, VA) plus 10% fetal calf serum (FCS), 2 mM L-glutamine, 10 mM HEPES, pH 7.4, 50 M ␤-mercaptoethanol, 50 units/ml penicillin, and 50 g/ml streptomycin as described (6).…”